Aggregation of otherwise soluble proteins into amyloid structures is a hallmark of many disorders, such as Alzheimer's and Parkinson's disease. There is an increasing evidence that the small aggregations, instead of ordered fibrillar aggregates, are the main structures causing toxicity. However, the studies on the small aggregation phase are limited due to the variety of structures and the complexity of the physiological environment. Here, we showed an engineered co-assembling oppositely charged amyloid-like peptide pair ([II]) as a simple tool to establish methodologies to study the mechanism and kinetics of aggregation and relate its aggregation to toxicity. The toxicity mechanism of [II] is through cell membrane damage and stress, shown with YAP and eIF2α, as in the amyloid protein-initiated diseases. Albumin is demonstrated as an extrinsic and physiologically relevant molecule in controlling the aggregation lag time and toxicity of [II]. This study represents a molecular engineering strategy to create simplistic molecular tools for establishing methodologies to study the aggregation process and kinetics of amyloid-like proteins in various conditions. Understanding the nature of protein aggregation kinetics and linking them to their biological functions through engineered peptides paves the way for future designs and drug development applications.
Keywords: aggregation kinetics; membrane damage; peptide co-assembly.